June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Fas inhibition preserves retinal and RPE phenotype in a chronic smoke exposure model of AMD
Author Affiliations & Notes
  • Marisol Cano
    Ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Natalie Thornton
    Ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Andrew J. Kocab
    ONL Therapeutics, Ann Arbor, Michigan, United States
  • David N Zacks
    University of Michigan W K Kellogg Eye Center, Ann Arbor, Michigan, United States
  • James T Handa
    Ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Marisol Cano None; Natalie Thornton None; Andrew Kocab ONL Therapeutics, Code E (Employment), ONL Therapeutics, Code I (Personal Financial Interest), ONL Therapeutics, Code P (Patent); David Zacks ONL Therapeutics, Code C (Consultant/Contractor), ONL Therapeutics, Code F (Financial Support), ONL Therapeutics, Code P (Patent); James Handa None
  • Footnotes
    Support  NIH R42 EY029625-02 “Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD” The goal of this STTR grant is to determine the extent that Fas inhibition prevents RPE and photoreceptor cell death in dry AMD.
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1132. doi:
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    • Get Citation

      Marisol Cano, Natalie Thornton, Andrew J. Kocab, David N Zacks, James T Handa; Fas inhibition preserves retinal and RPE phenotype in a chronic smoke exposure model of AMD. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1132.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the western world. While treatment is available for the neovascular (wet) form of the disease, no therapy exists for atrophic AMD. RPE cell death is a well recognized change in dry AMD. Cigarette smoke and a high fat diet (HFD) contribute to AMD pathobiology in part, by causing RPE injury and cell death, which can impair photoreceptor function to decrease vision. One known cell death pathway is mediated through Fas signaling, which can also induce inflammation. The purpose of this study was to test the extent that treatment with a Fas inhibitor preserves retinal and RPE phenotype and function in mice given a HFD and chronic cigarette smoke exposure

Methods : 2-month-old apoB100 mice were exposed to filtered air or cigarette smoke (CS) 5h/day for 6 months in a smoking chamber and fed a HFD consisting of 60% fat, 20% protein, and 20% carbohydrate. Mice were evaluated by fundus photography and ERGs before and after CS exposure. After 3.5 and 5 months of daily smoking, mice received an intravitreal injection of the Fas inhibitor in one eye and vehicle in the contralateral eye. At 6 months, eyes were collected for protein, and RPE and retinal flat mounts for immunofluorescence microscopy.

Results : Fas inhibition mitigated changes in RPE cell shape that develop with CS exposure, as measured by the cell aspect ratio, especially in the posterior fundus (Fas inhibitor 1.06 vs Vehicle 1.15; p≤ 0.01). Caspase 8 activity, as a measure of RPE death, was decreased in mice treated with the Fas inhibitor (1.54 RFU/cell) compared to vehicle (2.39 RFU/cell; p ≤ 0.05). The number of IBA1 labeled cells in retinal flat mounts were also decreased after ONL treatment compared to controls (p≤ 0.05). While aging decreased the a and b wave amplitudes, both smoking and Fas inhibition had minimal impact on the ERG signal.

Conclusions : Chronic cigarette smoke exposure of apoB 100 mice induced RPE morphology changes, apoptosis, and retinal inflammation. These changes were mitigated by Fas pathway inhibition. Targeting programmed cell death through Fas receptor inhibition provides a potential treatment approach for AMD by inhibiting RPE death and reducing retinal Inflammation.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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